Repeated exposure to psychostimulants, such as cocaine and amphetamine, produce an augmentation in the motor-stimulant response that increases with time, a phenomenon known as behavioral sensitization. Repeated exposure to stressful stimuli also produces an enhancement in the locomotor response to subsequent psychostimulants. the neurochemical changes underlying behavioral sensitization have focused on the mesocorticolimbic dopamine system, including the dopamine cell bodies in the ventral tegmental area (VTA) and projections to the medial prefrontal cortex (mPFC) and nucleus accumbens (NAcc). Recent cross-sensitization studies using in vivo microdialysis show that, in general, repeated stress or repeated cocaine augments the cocaine- or stress-induced increase in extracellular dopamine levels in the NAcc, while in the mPFC, an apparent tolerance to subsequent stimuli occurs. The augmentation in dopamine levels in the NAcc is known to be associated with behavioral sensitization but the inhibitory role of mPFC dopamine on locomotor activity has not been examined in the context of behavioral sensitization. The present studies propose to test the hypothesis that the apparent tolerance of mPFC neurons to subsequent stimuli contributes to the hyperlocomotion and associated increase in dopamine transmission in the NAcc in rats sensitized to repeated stress or cocaine. the first goal of this proposal is to characterize the changes that occur in extracellular dopamine levels in the mPFC following repeated footshock stress and repeated cocaine. In addition to measurement of basal dopamine levels in rats administered repeated stress and cocaine, in vivo dialysis measurements of mPFC extracellular dopamine levels will be performed following early, middle, and late withdrawal periods to determine if there are temporal changes in the tolerance effect. Secondly, mechanisms that may be mediating the tolerance effect in the mPFC will be examined in both the mPFC terminal field and in the dopamine cell body region in the VTA. The terminal field will be examined by local perfusion of K+, amphetamine, and cocaine through the dialysis probe. Additionally, dopamine reuptake will be tested in vitro in mPFC synaptosomes. Regulation by neurotransmitters in the VTA will be investigated by intra-VTA injection of NMDA, substance P and opioid agonists, and neurotensin, which modulate mPFC dopamine transmission. The final goal of this proposal is to determine the role of mPFC dopamine in the development and expression of behavioral and neurochemical sensitization. The first approach is to destroy mPFC dopamine terminals prior to repeated stress and cocaine treatment, and the second approach is to locally administer D1 and D2 receptor agonists into the mPFC just prior to a cocaine challenge to determine whether these treatments alter the levels of extracellular dopamine in the NAcc and associated increase in locomotor activity. Elucidation of the interactive role of mPFC dopamine in mediating sensitization to stress and cocaine has potential implications for understanding idiopathic as well as stress- and psychostimulant-precipitated psychoses, including paranoid schizophrenia, panic disorder, and posttraumatic stress disorder.